The functional role of the caspase cell death family in neurodegeneration, in particular ALS, has been clearly demonstrated. We have shown that caspases-1 and -3 are regulated at the transcription level in the mutant SOD1G93A transgenic ALS mouse model. Caspases-1 and -3 are specifically activated in ventral horn neurons in this mouse model. Adding relevancy to this finding, caspase-1 and -3 activation have been demonstrated in spinal cord of humans with ALS. Caspase inhibition, either by the caspase-1 dominant negative transgene, or by administration of the broad caspase inhibitor zVAD-fmk, slows disease progression and delays mortality in mutant SOD 1G93A mice. The broad goal of this study is to expand our understanding of the molecular and cellular pathways mediating neuronal cell death. This knowledge should contribute to the rational development of improved therapeutics for ALS. With this goal in mind we wish to evaluate the cell autonomous and non-cell autonomous signals modulating disease progression in ALS. The aims of this study include: 1) Evaluate the non-cell autonomous functional interaction between caspase-1 and iNOS in ALS mice. A detrimental feedback ioop appears to play a role between caspase-1-generated mature IL-1B and iNOSgenerated NO. 2) Caspase-1 and caspase-3 are regulated at the expression and activation levels. The regulation of additional caspases will be evaluated. 3) Evaluate a potential therapeutic role for minocycline in ALS. Investigate the mechanisms of minocycline-mediated neuroprotection. 4) Since neuroprotection conferred by caspase inhibition and Bcl-2 over expression occurs by acting at different stages of the cell death pathway, we hypothesize that the combination of caspase inhibition and Bcl-2 over expression will provide greater neuroprotection than either alone. A proper knowledge of the caspase-mediated pathways will aid in designing rational pharmacotherapy. Since the mechanisms of cell death in these devastating diseases appear to be shared, furthering the understanding of the mechanisms of neurodegeneration in ALS will likely result in benefits to other neurodegenerative diseases such as Huntington's, Parkinson's, and Alzheimer's disease.